We recently discovered that RGS14 is a novel mediator of hippocampal-based learning/memory. We find that RGS14 is expressed predominantly in brain, specifically within dendrites/neurites of hippocampal neurons important for learning/memory (i.e. pyramidal cells of the CA1/CA2 region). Our novel mice lacking the RGS14 gene/protein (RGS14-KO) exhibit a marked enhancement of spatial learning/memory and novel-object recognition and of long-term potentiation (LTP) of postsynaptic neurotransmission in CA1 neurons. These findings strongly suggest that RGS14 regulates signaling events critically important for hippocampal-based learning/memory. However, the molecular and cellular actions of RGS14 in hippocampal neurons remain poorly defined. We find that RGS14 binds Ric8A, an unconventional guanine- nucleotide exchange factor activator for G1i, and also to inactive Gi11/3-GDP, active H-Ras and Rap2 and their effectors the Raf kinases. In cells, RGS14 co-localizes with its binding partners at the plasma membrane to inhibit stimulated Ras/Raf/Erk signaling. When complexed with its partners in cells, RGS14 is phosphorylated at unknown site(s) with unknown functional consequences. Of note, RGS14 partners H-Ras, Rap2, Gi and linked Erk pathways regulate synaptic plasticity associated with learning/memory in hippocampal neurons including neurite outgrowth, dendritic remodeling, and trafficking of glutamate receptors. My working hypothesis is that RGS14 is a tightly regulated scaffolding protein that integrates unconventional Gi and H-Ras/Raf/MAPkinase signaling events important for synaptic plasticity involved with learning, memory and cognition in the hippocampus. Our Specific Aims will be to: Aim 1. Determine the protein/protein interactions and molecular mechanisms by which RGS14 integrates unconventional Ric8A/Gi1 and H-Ras/Rap2/Raf kinase signaling. Aim 2: Determine sites on RGS14 that are phosphorylated when complexed with Gi11/3, H- Ras or Rap2 in cells, the involved kinases, and how phosphorylation impacts RGS14 signaling. Aim 3: Determine roles for RGS14 in regulating molecular and physical markers of H- Ras/Raf/MAPkinase-directed synaptic plasticity in hippocampal neurons. Aim 4: Determine roles for RGS14 in regulating postsynaptic neurotransmission and linked behaviors that result from H-Ras/Raf/Erk-directed synaptic plasticity in the hippocampus Rap/MAPkinase signaling events and the morphology of primary hippocampal neurons. Impact: These studies will provide key insight about RGS14 as a novel regulator and integrator of neurotransmitter signaling events that modulate neuronal plasticity, learning and memory. PUBLIC HEALTH RELEVANCE: These studies will define novel molecular changes and underlying mechanism that occur in brain cells during normal physiological processes like learning and memory, and pathological processes such as Alzheimer's disease, other neurodegenerative diseases and epilepsy/seizures.